CN102105151B - Use of CDK inhibitor for treatment of glioma - Google Patents
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Abstract
The invention provides a lowmolecular weight ATP-competitive CDK inhibitor able to cross the blood brain barrier for use in the treatment of malignant glioma and, in particular, of glioblastoma. The compound can be administered together with one or more agents selected from the group consisting of cytotoxic or cytostatic agents and ionizing radiation.
Description
Technical field
The present invention relates to can be through competitive CDK (cyclin-dependent kinase) inhibitor for treating of the low-molecular-weight ATP-Response in Patients with Gliomas of blood brain barrier by using.
Background technology
Glioblastoma is height invasive and neural destructive tumor, and it has aggressive performance most is glioblastoma.A class cancer contained in term " glioma ", comprises astrocytoma, oligodendroglioma, few astrocytoma and ependymoma.The most widely used classification of glioma and hierarchy plan are the schemes of World Health Organization (WHO), wherein according to the differentiation line of their hypothesis, come to glioma classification, namely according to them, whether show that the feature of sternzellen, oligodendroglia or ependymocyte is classified.The pernicious degree according to them, be divided into I to IV level by them.Glioblastoma (GBM) is categorized as IV level glioblastoma multiforme.
Glioblastoma is modal primary brain tumors in the adult.In the U.S., be diagnosed as every year in 18,000 patients of pernicious primary brain tumors and surpass half and there is GBM.GBM is the cellularity tumor that a kind of anaplastic is very strong, has very high proliferation index, blood capillary propagation and focal necrosis.S&S depends on several factors (size, the speed of growth, the position of tumor in brain), the change that main manifestations is headache, epilepsy, neurological defect, the mental status.The prognosis of GBM remains very poor.For Most patients, life span is less than 2 years.Karnofsky performance state (KPS) is one of most important Prognostic Factors: the survival of patients of KPS>70 probability of 18 months is approximately 18%, and the patient that the KPS score is lower by comparison only has 13%.Idiopathic GBM is formed by glial cell, generally has the clinical history that is less than 6 months, more common in the gerontal patient, and has the minicell histology.Secondary cases GBM is formed through several months or several years by preformed rudimentary astrocytoma, the younger people of major effect, and have the giant cell histology.
The research that gliomatous molecular biology is this disease provides new understanding, and controlling the Cell signal transduction pathway imbalance by molecular targeted therapy becomes new orientation treatment.
Complicated hereditary change is relevant with the generation of constitutional and Secondary cases GBMs, in constitutional and time property sent out tumor, has lost identical genetic approach.
The main path relevant with the GBM pathogenesis has two kinds of [Rich JN, Bigner DD.NatRev Drug Discov 2004; 3 (5): 430-46].The first is the signal pathway by tyrosine kinase growth factor receptors mediation: in nearly all GBMs, the cascade of ras-MAP signal transduction of kinases is activated, and Akt is activated in about 70% GBMs.Really, the amplification of a lot of tyrosine kinase receptors [people such as Puputti M, Mol Cancer Res 2006 have also been reported; 4 (12): 927-934].
These pathology and much in other people cancer normal interrupted the second approach be RB-CDK-CDKI (cyclin-dependent kinase inhibitor) regulating loop: the disappearance of INK4A (also referred to as p16) detected in the GBMs at 40-57%, identified the disappearance of tumor inhibitor retinoblastoma (RB) in the GBMs of 14-33%.Stack up has detected variation [Zhu Y and the Parada LF.Nature Reviews Cancer 2002 of INK4A/CDK2/RB in the glioblastoma multiforme that surpasses 80% GBMs and 50%; 2:616-626].
The treatment of current GBM selects to comprise operation, X-ray therapy and chemotherapy.The most widely used medicine is carmustine, lomustine, vincristine, procarbazine, carboplatin, etoposide and Irinotecan.Use the new auxiliary or complementary therapy of these medicines to demonstrate the disease free survival time that can extend (disease-free survival), but can not extend total time-to-live.
Now, share temozolomide (TMZ) and X-ray therapy (RT) and become the new new nursing standard of diagnosing out GBM patient, compare with alone RT and aspect the time-to-live, having far reaching clinically to improve that (be 15 months with patient's mean survival time of TMZ/RT treatment, the patient of alone RT treatment is 12 months; 2 annual survival rates of TMZ/RT group are that 26%, RT group is 10%.
Although successfully introduced TMZ, the clinician still unanimously thinks, should further study the development of gliomatous new active medicine.Really, still fail to meet treating the medical need of gliomatous new active drug.The invention solves this problem.
Summary of the invention
The invention provides a kind of low-molecular-weight compound, it can pass blood brain barrier, can suppress the two kind main paties relevant with the glioma pathogenesis by the signalling channel that suppresses CDKs and tyrosine kinase growth factor receptors-mediation, and effectively suppress glioma propagation.
The compound of the present invention that shows desired activity is a kind of pyrazolo quinazoline, is designed for targeting in the ATP of protein kinase bag.It is the effective ATP-competitive inhibitor of CDKs that this compound has demonstrated.Unexpectedly, we have found that, described compound demonstrates significant inhibition effect to TRKA (Thropomyosin receptor kinase A).In addition, we have found that, described compound can enter in brain in a large number.
Consider its biological activity, the research that compound of the present invention is suffered from gliomatous patient crowd for treatment provides a kind of new approach.
Detailed Description Of The Invention
Aspect first, the present invention relates to the compound of formula (I)
or the acceptable salt of its pharmacy, be used for the treatment of the method for glioblastoma.
Term used herein " glioblastoma " or " glioma " comprise astrocytoma (particularly glioblastoma), oligodendroglioma, few astrocytoma, ependymoma and the mixed type colloid-neuroma (tumor that shows neural and colloid key element, for example, ganglioglioma, non-embryo's formative neuroepithelioma) and be derived from the tumor (for example, paraganglioma, nervus centralis Gangliocytoma) of neurocyte.
In preferred embodiment of the present invention, the compound of formula defined above (I) is used for the treatment of the method for glioblastoma (GBM).
The chemical name of the compound of formula (I) is 8-[4-(4-methyl-piperazine-1-yl)-phenylamino]-Isosorbide-5-Nitrae, 4-trimethyl-4,5-dihydro-1 h-pyrazole [4,3-h] quinazoline-3-formic acid methyl nitrosourea.It can WO2004104007 is described prepares, and has protein kinase inhibiting activity, therefore can be used as antitumor agent and is used for the treatment of.Particularly, the preferred preparation method of the compound of formula (I) is described in the embodiment 58 of above-mentioned international patent application.
The acceptable salt of pharmacy of the compound of formula (I) comprises and inorganic or organic acid acid-addition salts, these acid for example are, nitric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propanoic acid, glycolic, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, isethionic acid and salicylic acid etc.
In claimed scope of the present invention, all possible isomer of compound of use formula (I) and their the acceptable bioprecursor of mixture, metabolite and pharmacy (also referred to as prodrug).Prodrug is covalently bound compound arbitrarily, and it discharges the active parent drug of formula (I) in vivo.
The compound of the formula (I) for the treatment of effective dose can be applied to this individuality when definite individuality suffers from disease or undesirable disease, and described disease or disease can benefit by described compounds for treating.As the part of individual disease or Illnesses Diagnoses, medical science or clinical staff can be made this decision.This compound also can be for preventing these diseases, and this can be considered as reducing the individual probability of suffering from one or more diseases.
The compound of " treatment effective dose " used herein refers to the amount that is enough to reach its expection purpose.Realization based on desired effect, effective dose fixes in those skilled in the art's limit of power really.Effective dose depends on various factors, includes but not limited to, the development degree of individual build and/or individual the disease that takes a disease or undesirable disease.Effective dose also depends on whether this compound is applied to individuality with single dose or timing in time.
The compound of formula of the present invention (I) is intended to be used for the treatment of individuality.Term used herein " individuality " comprises mammal and nonmammalian.Mammiferous example includes but not limited to, any member of mammal: people, inhuman primates be orangutan for example, and other apes and monkey class; Farm-animals is cattle, horse, sheep, goat, pig for example; The livestock animal is rabbit, Canis familiaris L. and cat for example; Laboratory animal comprises Rodents, for example rat, mice and Cavia porcellus, etc.The example of nonmammalian includes but not limited to, bird, fish etc.
Term used herein " treatment " comprises realizes the treatment benefit.The treatment benefit refers to elimination or improves the potential disease for the treatment of.For example, in the cancer patient, the treatment benefit comprises elimination or improves potential cancer.Simultaneously, it is also to have realized the treatment benefit that elimination or improvement one or more physiology symptoms relevant with potential disease are consequently observed improvement in the patient, although in fact the patient is still tormented by potential disease.
Another object of the present invention is a kind of therapeutic combination, the compound that comprises formula defined above (I), with (b) one or more are selected from antitumor agent and the ionizing radiation of cytotoxicity or cell growth inhibition chemicals, is used for the treatment of the method for glioblastoma.
Exemplary cytotoxicity or cell growth inhibition chemicals comprise antibiotics, alkylating agent, antimetabolite, anti-microtubule agent, hormone medicine, immunizing agent, the interferons medicine, cyclooxygenase-2 inhibitors (for example, cox 2 inhibitor), matrix metallo-proteinase inhibitor, the telomerase inhibitor, tyrosine kinase inhibitor, antibiosis growth factor receptor body medicine, anti-HER agent, the anti-EGFR agent, anti-angiogenic agent (for example, angiogenesis inhibitor), farnesyl transferase inhibitor, ras-raf signal transduction pathway inhibitor, cell cycle inhibitor, other cdks inhibitor, the tubulin binding agent, the topoisomerase I inhibitor, topoisomerase I I inhibitor etc.
In a particularly preferred embodiment according to the invention, cytotoxicity or cell growth inhibition chemicals are temozolomide (temozolomide).
Ionizing radiation, also referred to as X-ray therapy, be generally used for field of cancer, comprise and there is enough photons for the Ionized energy of key, for example, derive from the α of radioactive nucleus-, β-and gamma-radiation, and X-ray.
The present invention also relates to a kind of pharmaceutical composition, the compound that comprises formula as defined above (I) mixes with pharmaceutically acceptable carrier, diluent or excipient, is used for the treatment of glioblastoma.
In another embodiment, pharmaceutical composition of the present invention also comprises one or more antitumor agent and ionizing radiation that is selected from cytotoxicity or cell growth inhibition chemicals.In an especially preferred embodiment, described chemicals is the temozolomide.
Generally prepared by the pharmaceutical composition that comprises compound of the present invention, and use according to conventional methods with suitable medicament forms.
For example, the Peroral solid dosage form form can comprise the diluent together with reactive compound, for example, and lactose, dextrose, disaccharide (saccharose), sucrose, cellulose, corn starch or potato starch; Lubricant, for example, Silicon stone, Talcum, stearic acid, magnesium stearate or calcium and/or Polyethylene Glycol; Binding agent, for example starch based, arabic gum, gelatin, methylcellulose, carboxymethyl cellulose or polyvinylpyrrolidone; Disintegrating agent, for example starch, alginic acid, alginate or primojel; Foaming mixture; Dyestuff; Sweeting agent; Wetting agent is lecithin, Polysorbate, lauryl sulfate (ester) for example; With non-activity commonly used in pharmaceutical preparation and the material of pharmacology's non-activity.Can prepare in a known way by these pharmaceutical preparatioies, for example, and by the method for mixing, granulation, film-making, sweet tablet or film Cotton seeds.
The oral liquid dispersion liquid given can be, for example syrup, Emulsion or suspension.
For example, syrup can comprise the disaccharide as carrier, or disaccharide and glycerol and/or mannitol and Sorbitol.
Suspension and Emulsion can comprise, as natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethyl cellulose or the polyvinyl alcohol of carrier example.
In the treatment application, with about 10mg/m every day
2-600mg/m Yue
2the dosage level of body surface area by the compound administration of formula (I) in individuality.About 20mg/m
2-200mg/m
2dosage level formed suitable especially scope.For becoming individual human, the about 1000mg of the about 20mg-of every dosage, the more preferably about 400mg of the about 60mg-of every dosage, the dosage of 1-28 days can be used as nonrestrictive example continuously.Other examples of application program are: use the 1-7 days every days at 2 cycles; Use the every day in 1-4 days each week of continuous 3 weeks at 4 cycles; Use the 1-14 days every days at 3 cycles; 1-7 and 15-21 days every days at 4 cycles use.
If necessary, can use than above-mentioned open lower or higher dosage.But, can regulate these dosage according to a lot of variablees, these variablees be not limited to the activity of used compound, the disease for the treatment of, method of application, therapeutic scheme, individual patient needs, sanatory severity and doctor's judgement.Above-mentioned scope is only suggestive, because the variables number of individual treatment scheme is very large, departs from considerably these recommendations much.
For the present invention is described better, but not it is carried out to any restriction, provide now the following example.
The accompanying drawing summary
Fig. 1 has shown protein expression in the cell of not treating cell (C) and processing with the compound (T) of the formula (I) of two kinds of dosage (1 and 3 μ M).Analyzed the protein (cdc6 relevant with controlling cell cycle progression; Cyclin A and cell periodic protein B) and the phosphorylation of the direct substrate of CDK2 (RB albumen).
Fig. 2 has shown protein expression in the cell of not treating cell (C) and processing with the compound (T) of the formula (I) of 3 μ M.What show is the amount of the p44/42MAPK of the TRKA of phosphorylation, total TRKA albumen, phosphorylation and AKT and total p44/42MAPK.
Fig. 3 has shown the time-to-live of the mice of the neuroglial cytoma strain with intracranial implantation: the mice (dotted line) of the compounds for treating of untreated mice (black line), use formula (I).
Embodiment
The kinase whose scintillation proximity assay of embodiment 1. (SPA) mode
This analysis can be measured the inhibition of test-compound to the kinase activity of certain enzyme, can the different kinases of parallel assay.
Under the ATP that comprises γ 33-ATP tracer exists, by specific kinases, biotinylated substrate is turned to phosphorylation.When reaction finishes, then with streptavidin, coated SPA pearl catches this phosphorylated substrate.Add the 5M CsCl solution that density is higher, this mixture is cultivated 4 hours.This can cause the SPA pearl to be floated to the top of the CsCl solution that comprises unmixing radiolabeled ATP.Measure the degree of phosphorylation with beta-counter.
In these are measured, the compound of formula (I) demonstrates has the active (IC of effective inhibition to CDK2/ cyclin A complex
50=45nM), simultaneously to closely-related CDKs, CDK1, CDK4 and CDK5 also demonstrate activity (IC
50be respectively 398,160 and 265nM), Thropomyos in receptor kinase A (TRKA) is also had to activity (IC50=53nM).
The level of the compound of embodiment 2. brain Chinese styles (I)
Continuous 6 days the formula of the oral dose with 60mg/kg (I) compound treat Han Wistar rat.After administration in the 6th day the 2nd and within 6 hours, put to death these animals.Take out brain and blood plasma when putting to death.Blood is positioned in the plastic tube of heparinization, is held in ice-water-bath, then centrifugal (10 minutes, at 4 ℃ of lower 1200g).Brain and plasma sample are kept in the refrigerator of-80 ℃, until analyze.Level with LC/MS/MS analysis mode (I) compound.
After administration 2 and 6 hours, the brain level result of the compound of formula (I) was average out to 88.9 and 69.4nmoles/gr tissue.In blood plasma, corresponding level is respectively 9.8 and 8.4nmoles/mL.Suppose that density equals 1, the brain level of the compound of formula (I) than the high 6.1-9.6 of blood plasma level doubly.
Embodiment 3., after the compound of the formula (I) of using [14C]-labelling to Sprague Dawley rat, determines radioactive distribution in brain by the autoradiography luminography
By single oral (radioactive dosage is 100mCi/kg for the maleate of 20mg/kg, about 3.7MBq/kg), (Sprague Dawley rat, from Charles River Italy to give 6 male white rats; During administration, body weight is 259-273g) use the compound (specific activity is 5 μ Ci/mg, indoor preparation) of the formula (I) of [14C]-labelling.
Within 2,6 and 24 hours after using, put to death animal (each selected time is put to death 2 animals), after excision, estimate the increased radioactivity of the material relevant to compound in complete brain.The autoradiography luminography is for estimating the quantitative increased radioactivity of brain.
Estimate increased radioactivity in the blood of also collecting in the animal from putting to death and blood plasma.Determine the radioactive level in blood and blood plasma by liquid scintillation counting (LSC).
Table 1 has shown rat single oral administration (20mg/kg) distribution of the compound of the formula (I) of 14C-labelling afterwards.
Table 1
The in vitro effects of the compound of embodiment 4. formulas (I) to neuroglial cytoma
By SF-268, SF-295, SF-539 and U251 cell strain are cultivated in the RPMI 1640 that has added 10%FCS and 2mM glutamine, and the U-87MG cell strain is being added to 10%FCS, in the EMEM of 2nM glutamine and 1%NEAA, cultivate.For all experiments, with 1x10
4/ cm
2density implant cell, with the natural law after this compounds for treating, be official hour, then in reported time collection.
the inhibition of on cell proliferation
After treatment 72 hours, washed cell counting.Measure cell proliferation by adenosine triphosphate monitoring system in cell.Cell proliferation and compared with control cells are compared.Calculate the concentration (IC that suppresses 50% cell proliferation
50).
the analysis that BrdU mixes.
In last hour for the treatment of in 24 hours, the ultimate density of take joins BrdU (the bromo-2 ' BrdU of 5-) in cell culture medium as 30 μ M.Use the PBS washed cell, fixing in 70% ethanol, and be stored in-20 ℃.When analyzing, cell centrifugation is separated, use the PBS liquid of 1%FCS and wash 20 minutes with the DNA of HCl 2N degeneration.At Na
2b
4o
70.1M in pH 8.5 after washing 1 time, with the PBS+1%FCS hydroponics cell of 0.5% Tween20 15 minutes, then centrifugalize.The not yoke that precipitation is suspended in again to the dilution in 1: 10 of 150 μ l closes in anti-BrdU monoclonal antibody (Becton Dickinson), and at room temperature cultivates 1 hour.Wash 1 time in PBS after, then cultivate with 0.5%Tween20; Then add secondary antibodies (1: 50 rare FITC-yoke close goat anti-mouse globulin (Jackson Lab.)).After at room temperature 1 hour, then rinse cell, and redye (2 μ g/ml+12.5 μ g/ml are without the RNAse of DNAse) with propidium iodide and spend the night, then pass through facs analysis.
acridine orange dyes to estimate autophagy.
Cultivating last 15 minutes add acridine orange (1 μ g/ml) in cell, collecting cell then, and with the PBS washing, and by their fluorescent radiation of facs analysis.Acridine orange moves freely through biomembrane, still, when in Cytoplasm and nucleus, sends bright green and bolarious fluorescence; Show shiny red in the acid cavity produced at autophagy.
The report the test of all these analyses is in table 1.The compound of formula (I) all has activity for all tested neuroglial cytomas (the first hurdle): it can suppress propagation, IC
50scope is 1.4-5.4 μ M (the second hurdle); It synthesizes and has effect for DNA, and the inhibition scope that BrdU is mixed of measuring is 39-92% (third column), and it can induce autophagy (the 4th hurdle) in the cell of 36-70%.It is reported, such tumor is replied preferential generation autophagy to chemotherapy and γ-radiation, but not apoptosis.
Table 2
Glioma IC
50(μ M) %BrdU suppresses autophagy %
U251 2.8+/-0.8 74 58(3μM)
SF539 1.4+/-0.5 39 35(6μM)
SF258 2.5+/-0.6 78 70(3μM)
SF295 5.4+/-0.6 74 68(3μM)
U87MG 1.6+/-0.8 92 50(3μM)
Embodiment 5. is by the model of action of the compound of western blot analysis bounds evaluation (I)
By adding SDS sample buffer (0.125M Tris-HCl pH6.8,5%SDS) to dissolve cell to be processed.By sample be heated to 95 ℃ 5 minutes, then with ultrasonic 2000 ARTEK, carry out sonication.With 13,000 RPM, the cell centrifugation dissolved is separated 10 minutes.Determine the amount of protein with BCA buffer (Pierce) and BSA standard curve.Every hole is written into 20 μ g protein extracts, and separates by SDS-PAGE gel 7.5-10% (PAGE-PLUS 40% concentrate AMRESCO).Comprising 25mM Tris HCl pH 8.3, in the buffer of 192mM glycine and 20% methanol, this gel is being stained with on nitrocellulose filter paper (Hybond Amersham).At the TBS (comprising 0.1% Tween 20) of 5% low fat milk (TBS-T) in liquid, by this filter paper at room temperature saturated 2 hours, then under 4 ℃ by elementary monoclonal body overnight incubation, then in TBS-T, wash, and cultivate with secondary anti-mouse antibodies.Form band with " Super Signal West Pico " Pierce observation post.
The result obtained in all subject cell strains shows, the compound of formula (I) can disturb the whole two kind main paties relevant with glioma.In fact, do not rely on the situation of Rb approach, all observed the label relevant to cell cycle and reduce in all neuroglial cytoma strains.For example, Fig. 1 has shown in the compound treatment U251 cell of 24 hours by the formula (I) of two kinds of dosage and has obtained result.Obviously, strong inhibition Rb phosphorylation and cdc6, cyclin A and B1 express.
The compound of also having estimated formula (I) suppresses the ability of the approach of tyrosine kinase growth factor receptors mediation.Fig. 2 shows, in the processing SF-539 cell of 6 hours, has suppressed the phosphorylation of TRKA receptor and downstream egg white matter in MAPK and AKT approach.
The compound of embodiment 6. formulas (I) is to acting in gliomatous body
antitumor effect to human glioma's heteroplastic transplantation model
Will be from the BaIb of Harlan (Italy), the Nu/Nu male mice is held in the cage with paper filter lid, by food and the sterilization of sleep articles for use, and by the water acidify.Subcutaneous implantation 2.5x10 in athymic mouse
6u251 human glioma cell (from American Type CultureCollection).The continuous 10 days volumes with 10ml/kg, the dosage of 40mg/kg, every day 2 times (BID), use the compound of formula (I) by oral route.Within every 3 days, measure tumor growth and body weight.Estimate tumor growth by caliper.Record two diameters, calculate tumor weight according to following formula: x is wide for length (mm)
2/ 2.Based on losing weight to estimate toxicity.
The result that is reported in table 2 shows, the compound of formula (I) has produced obvious antitumous effect in human glioma's heteroplastic transplantation model U251.
Table 3
| Treatment | Maximum tumor growth suppresses (%) | Toxicity |
| The compound 40mg/kg of formula (I) | 80 | 0/8 |
the effect of the glioma tumor model that intracranial is implanted
Anaesthetize the animal that will carry out operation technique according to one of following proposal, i.e. ketamine, 80-100mg/kg i.p.+Xilazin:10mg/kg i.p.; Different fluorane: 1.5-2%.Anaesthetize the 6-8 athymism male nude mouse in age in week, be positioned under stereotaxic instrument, fixing with the ear rod gently, and stretch in head holder.The skin of the topping that vertically (is parallel to ear), expose the skull of mice.Use X and the Y-axis controller of this device, identify bregma (section between the middle and front hat seam of arrow-shaped, to carry out to the injection in cerebral nucleus) and lambda (in the middle of sagittal suture and the section between rear hat seam, to carry out to the injection in cerebellum), as 0 point.Following coordinate is set in this device and identifies injection point.Use micro-brill, at desired point, make aperture.Just before will injecting, with Hamilton syringe pump cell (2-5ml usually) (carrying out the short mixing of cell before suction, to prevent cell precipitation).By pointing to this hole, Z axis is fixed to 0 point, syringe is inserted in brain gently, until arrive correct coordinate (3.0mm is dark).Speed injection U251 cell with 1 μ l/ minute.Before shifting out, syringe is placed 5 minutes at Kong Zhongzai, to prevent the cell suction.Seal this hole with bone wax, and close wound with the aseptic minor operation clamp of closing wound.After operation finishes, the recovery of monitoring mice, until revive fully.
The result of Fig. 3 shows, with the control mice of vehicle treatment, compares, and when the compound bid OS treatment (bid OS) of the formula (I) with the dosage of 40mg/kg, has intracranial and implants the mouse survival time of human glioma's model and increased by 30%.
Claims (5)
1. the compound of formula (I)
Or the purposes of the acceptable salt of its pharmacy in the medicine for the preparation of the treatment glioblastoma.
2. the therapeutic combination purposes in the medicine for the preparation of the treatment glioblastoma, wherein said therapeutic combination comprises compound and the temozolomide as the formula (I) of claim 1 definition.
3. according to the purposes of claim 2, wherein said medicine and ionizing radiation coupling.
4. the pharmaceutical composition purposes in the medicine for the preparation of the treatment glioblastoma, wherein said pharmaceutical composition comprises the compound of formula (I) and mixing of pharmaceutically acceptable carrier, diluent or excipient as claim 1 definition.
5. according to the purposes of claim 4, wherein said medicine and temozolomide and/or ionizing radiation coupling.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08161323 | 2008-07-29 | ||
| EP08161323.4 | 2008-07-29 | ||
| PCT/EP2009/059747 WO2010012733A1 (en) | 2008-07-29 | 2009-07-28 | Use of a cdk inhibitor for the treatment of glioma |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102105151A CN102105151A (en) | 2011-06-22 |
| CN102105151B true CN102105151B (en) | 2013-12-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801292593A Active CN102105151B (en) | 2008-07-29 | 2009-07-28 | Use of CDK inhibitor for treatment of glioma |
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| Country | Link |
|---|---|
| US (1) | US8946226B2 (en) |
| EP (1) | EP2323664B1 (en) |
| JP (1) | JP5677296B2 (en) |
| CN (1) | CN102105151B (en) |
| ES (1) | ES2532732T3 (en) |
| HK (1) | HK1153938A1 (en) |
| WO (1) | WO2010012733A1 (en) |
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| JP2012509859A (en) * | 2008-11-24 | 2012-04-26 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | CDK inhibitors for the treatment of mesothelioma |
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| KR101852169B1 (en) | 2010-05-20 | 2018-04-26 | 어레이 바이오파마 인크. | Macrocyclic compounds as trk kinase inhibitors |
| JP5925808B2 (en) * | 2011-01-26 | 2016-05-25 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | Tricyclic derivatives, their preparation and their use as kinase inhibitors |
| BR112013018515B1 (en) * | 2011-01-26 | 2021-06-29 | Nerviano Medical Sciences S.R.I | TRICYCLICAL PYRROL DERIVATIVES, PROCESS FOR THEIR PREPARATION AND USE AS KINASE INHIBITORS |
| CN110711188A (en) * | 2012-01-20 | 2020-01-21 | 德玛公司 | Use of substituted hexitols for the treatment of malignant tumors |
| EP2934564B1 (en) * | 2012-12-20 | 2018-05-23 | Lantmännen AS-Faktor AB | Antisecretory factor (af) for use in the treatment of glioblastoma |
| JP6914834B2 (en) | 2014-11-16 | 2021-08-04 | アレイ バイオファーマ インコーポレイテッド | (S) -N- (5-((R) -2- (2,5-difluorophenyl) -pyrrolidine-1-yl) -pyrazolo [1,5-a] pyrimidin-3-yl) -3-hydroxy Crystal form of pyrrolidine-1-carboxamide hydrogen sulfate |
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| SI3322706T1 (en) | 2015-07-16 | 2021-04-30 | Array Biopharma, Inc. | Substituted pyrazolo(1,5-a)pyridine compounds as ret kinase inhibitors |
| AU2016344058A1 (en) | 2015-10-26 | 2018-05-17 | Array Biopharma Inc. | Point mutations in Trk inhibitor-resistant cancer and methods relating to the same |
| US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
| TN2018000335A1 (en) | 2016-04-04 | 2020-01-16 | Loxo Oncology Inc | Liquid formulations of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide |
| BR112018070017A2 (en) | 2016-04-04 | 2019-02-05 | Loxo Oncology Inc | Pediatric Cancer Treatment Methods |
| PL3800189T3 (en) | 2016-05-18 | 2023-10-23 | Loxo Oncology, Inc. | Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide |
| TWI704148B (en) | 2016-10-10 | 2020-09-11 | 美商亞雷生物製藥股份有限公司 | Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors |
| JOP20190077A1 (en) | 2016-10-10 | 2019-04-09 | Array Biopharma Inc | Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors |
| JOP20190092A1 (en) | 2016-10-26 | 2019-04-25 | Array Biopharma Inc | PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF |
| WO2018136663A1 (en) | 2017-01-18 | 2018-07-26 | Array Biopharma, Inc. | Ret inhibitors |
| ES2948194T3 (en) | 2017-01-18 | 2023-09-01 | Array Biopharma Inc | Substituted pyrazolo[1,5-a]pyrazine compounds as RET kinase inhibitors |
| JOP20190213A1 (en) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | Macrocyclic compounds as ros1 kinase inhibitors |
| US11319323B2 (en) | 2017-08-11 | 2022-05-03 | Shengke Pharmaceuticals (Jiangsu) Ltd. | Substituted pyrazolo[4,3-H]quinazolines as protein kinase inhibitors |
| TWI812649B (en) | 2017-10-10 | 2023-08-21 | 美商絡速藥業公司 | Formulations of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile |
| TWI791053B (en) | 2017-10-10 | 2023-02-01 | 美商亞雷生物製藥股份有限公司 | Crystalline forms of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile and pharmaceutical composition thereof |
| CA3080157A1 (en) | 2017-10-26 | 2019-05-02 | Array Biopharma Inc. | Formulations of a macrocyclic trk kinase inhibitor |
| WO2019143994A1 (en) | 2018-01-18 | 2019-07-25 | Array Biopharma Inc. | Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors |
| CN111630054B (en) | 2018-01-18 | 2023-05-09 | 奥瑞生物药品公司 | Substituted pyrazolo [3,4-d ] pyrimidine compounds as RET kinase inhibitors |
| CN111971286B (en) | 2018-01-18 | 2023-04-14 | 阿雷生物药品公司 | Substituted pyrrolo [2,3-d ] pyrimidine compounds as RET kinase inhibitors |
| MA52218A (en) | 2018-03-29 | 2021-02-17 | Loxo Oncology Inc | TREATMENT OF CANCERS ASSOCIATED WITH TRK |
| CN117285467A (en) | 2018-07-31 | 2023-12-26 | 罗索肿瘤学公司 | Spray-dried dispersions and formulations |
| US11964988B2 (en) | 2018-09-10 | 2024-04-23 | Array Biopharma Inc. | Fused heterocyclic compounds as RET kinase inhibitors |
| US20220081438A1 (en) | 2018-12-19 | 2022-03-17 | Array Biopharma Inc. | Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases |
| WO2020131674A1 (en) | 2018-12-19 | 2020-06-25 | Array Biopharma Inc. | 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer |
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| WO2007090794A1 (en) * | 2006-02-10 | 2007-08-16 | Nerviano Medical Sciences S.R.L. | Combinations comprising a cdk inhibitor and a growth factor antibody or anti-mitotic |
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| US8518930B2 (en) * | 2008-07-29 | 2013-08-27 | Nerviano Medical Sciences S.R.L. | Therapeutic combination comprising a CDKS inhibitor and an antineoplastic agent |
| JP2012509859A (en) * | 2008-11-24 | 2012-04-26 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | CDK inhibitors for the treatment of mesothelioma |
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| WO2004104007A1 (en) * | 2003-05-22 | 2004-12-02 | Pharmacia Italia S.P.A. | Pyrazolo-quinazoline derivatives,process for their preparation and their use as kinase inhibitors |
| WO2007090794A1 (en) * | 2006-02-10 | 2007-08-16 | Nerviano Medical Sciences S.R.L. | Combinations comprising a cdk inhibitor and a growth factor antibody or anti-mitotic |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010012733A1 (en) | 2010-02-04 |
| ES2532732T3 (en) | 2015-03-31 |
| HK1153938A1 (en) | 2012-04-13 |
| WO2010012733A9 (en) | 2011-04-14 |
| US20110190311A1 (en) | 2011-08-04 |
| EP2323664A1 (en) | 2011-05-25 |
| US8946226B2 (en) | 2015-02-03 |
| EP2323664B1 (en) | 2015-01-07 |
| JP2011529467A (en) | 2011-12-08 |
| CN102105151A (en) | 2011-06-22 |
| JP5677296B2 (en) | 2015-02-25 |
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